Clinical Trials /

Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

NCT01886872

Description:

This randomized phase III trial studies rituximab with bendamustine hydrochloride or ibrutinib to see how well they work compared to ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether rituximab with bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in treating chronic lymphocytic leukemia.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Rituximab</span> and <span class="go-doc-concept go-doc-intervention">Bendamustine Hydrochloride</span>, <span class="go-doc-concept go-doc-intervention">Rituximab</span> and <span class="go-doc-concept go-doc-intervention">Ibrutinib</span>, or <span class="go-doc-concept go-doc-intervention">Ibrutinib</span> Alone in Treating Older Patients With Previously Untreated <span class="go-doc-concept go-doc-disease">Chronic Lymphocytic Leukemia</span>

Title

  • Brief Title: Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia
  • Official Title: A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients ( 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
  • Clinical Trial IDs

    NCT ID: NCT01886872

    ORG ID: NCI-2013-01220

    NCI ID: NCI-2013-01220

    Trial Conditions

    Stage I Chronic Lymphocytic Leukemia

    Stage II Chronic Lymphocytic Leukemia

    Stage III Chronic Lymphocytic Leukemia

    Stage IV Chronic Lymphocytic Leukemia

    Trial Interventions

    Drug Synonyms Arms
    Bendamustine Hydrochloride Bendamustin Hydrochloride, BENDAMUSTINE HYDROCHLORIDE, Cytostasan Hydrochloride, Ribomustin, SyB L-0501, Treanda Arm I (rituximab, bendamustine hydrochloride)
    Ibrutinib BTK Inhibitor PCI-32765, CRA-032765, IBRUTINIB, PCI-32765 Arm II (ibrutinib), Arm III (ibrutinib, rituximab)

    Trial Purpose

    This randomized phase III trial studies rituximab with bendamustine hydrochloride or
    ibrutinib to see how well they work compared to ibrutinib alone in treating older patients
    with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as
    rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used
    in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the
    growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
    stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some
    of the enzymes needed for cell growth. It is not yet known whether rituximab with
    bendamustine hydrochloride is more effective than rituximab and ibrutinib or ibrutinib alone
    in treating chronic lymphocytic leukemia.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine whether progression free survival (PFS) is superior after therapy with
    bendamustine (bendamustine hydrochloride) in combination with rituximab, ibrutinib alone, or
    ibrutinib in combination with rituximab in patients age 65 or older with previously
    untreated chronic lymphocytic leukemia (CLL).

    SECONDARY OBJECTIVES:

    I. To determine 2-year PFS in each of the three treatment arms. II. To determine which
    treatment arm produces superior overall survival (OS). III. To determine the complete
    response (CR) rate, complete and nodular partial response (CR/nPR) rate, and overall
    response (PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms.

    IV. To determine the impact of minimal residual disease (MRD)-negative disease at time of CR
    documentation and at 2 years on PFS and OS in each of the treatment arms.

    V. To determine duration of response after each of the three treatments and compare these
    treatment arms.

    VI. To determine toxicity and tolerability of the three treatment regimens. VII. To
    determine response and PFS of patients initially on the bendamustine in combination with
    rituximab arm who cross over to ibrutinib.

    VIII. To determine whether baseline cytogenetic markers, zeta-chain (TCR) associated protein
    kinase 70kDa (Zap-70) methylation, immunoglobulin variable region (IgVH) mutational status,
    or select deoxyribonucleic acid (DNA) mutations predict outcomes or time to response in
    these three arms.

    IX. To determine whether local fluorescent in situ hybridization (FISH) results for
    del(11q22.3) and del(17p13.1) are consistent with central analysis.

    X. To determine whether baseline micro ribonucleic acid (RNA) and gene expression markers
    are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2
    years versus not), as well as to explore changes in microRNA expression from baseline to
    post-treatment time points, with a focus on those with persistent lymphocytosis and relapse.

    XI. To determine whether eradication of MRD predicts longer duration of response with
    standard therapy and ibrutinib-based regimens.

    XII. To describe the baseline functional status, comorbid medical conditions, and number of
    medications of older CLL patients who meet criteria for therapy.

    XIII. To determine how functional status changes with therapy using baseline to 3-month
    evaluation and end-of-study/2-year evaluation; to determine whether this change is different
    among the treatment groups.

    XIV. To determine whether geriatric assessment variables known to be associated with
    chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity
    in the CLL population.

    XV. To assess whether the Fc fragment of IgG, low affinity IIIa, receptor (CD16a) (FCGR3A)
    polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus
    rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and
    progression-free survival (PFS).

    XVI. To assess whether complement component 1, q subcomponent, A chain (C1QA) polymorphism
    (rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS.

    OUTLINE: Patients are randomized to 1 of 3 treatment arms.

    ARM I: Patients receive rituximab intravenously (IV) on day 1 (day 0 course 1) and
    bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days
    for 6 courses in the absence of disease progression or unacceptable toxicity. Patients
    experiencing disease progression may crossover to Arm II.

    ARM II: Patients receive ibrutinib orally (PO) daily on days 1-28. Courses repeat every 28
    days in the absence of disease progression or unacceptable toxicity.

    ARM III: Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1,
    8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the
    absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up every 3 or 6 months for up to
    10 years.

    Trial Arms

    Name Type Description Interventions
    Arm I (rituximab, bendamustine hydrochloride) Active Comparator Patients receive rituximab IV on day 1 (day 0 course 1) and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II. Bendamustine Hydrochloride
    Arm II (ibrutinib) Experimental Patients receive ibrutinib PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib
    Arm III (ibrutinib, rituximab) Experimental Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must be diagnosed with CLL in accordance with International Workshop on
    Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the
    following:

    - >= 5 x 10^9 B lymphocytes (5000/uL) in the peripheral blood

    - On morphologic review, the leukemic cells must be small mature lymphocytes, and
    prolymphocytes must not exceed 55% of the blood lymphocytes

    - CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell
    population, which express the B cell surface markers of cluster of
    differentiation (CD)19 and CD20, as well as the T-cell antigen CD5; patients
    with bright surface immunoglobulin expression or lack of CD23 expression in >
    10% of cells must lack t(11;14) translocation by interphase cytogenetics

    - Patients must be intermediate or high-risk Rai stage CLL

    - Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus
    enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly

    - High risk (formerly Rai stage III/IV) is defined by fulfilling criteria for
    intermediate risk disease plus disease-related anemia (hemoglobin < 11 g/dL) or
    thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to
    autoimmune hemolytic anemia or thrombocytopenia

    - Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which
    includes at least one of the following criteria:

    - Evidence of marrow failure as manifested by the development or worsening of
    anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
    thrombocytopenia)

    - Massive (>= 6 cm below the costal margin), progressive or symptomatic
    splenomegaly

    - Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

    - Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
    therapy

    - Constitutional symptoms, which include any of the following:

    - Unintentional weight loss of 10% or more within 6 months

    - Significant fatigue

    - Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection

    - Night sweats > 1 month without evidence of infection

    - Prior teatment

    - Patients must not have had prior therapy for CLL (except palliative steroids or
    treatment of autoimmune complications of CLL with rituximab or steroids)

    - Treatment with rituximab and/or high dose corticosteroids for autoimmune
    complications of CLL must be complete at least 4 weeks prior to enrollment;
    palliative steroids must be at a dose not higher than 20 mg/day of prednisone or
    equivalent corticosteroid at the time of registration

    - Eastern Cooperative Oncology Group (ECOG) performance status 0-2

    - Patients with active hepatitis B defined by hepatitis B surface antigen positivity or
    core antibody positivity in the presence of hepatitis B DNA are not eligible for this
    study; patients with a positive hepatitis B core antibody but with negative hepatitis
    B DNA may participate, but must have hepatitis serologies and hepatitis B DNA
    monitored periodically by the treating physician

    - Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B
    serology; if patients receiving routine IVIG have core antibody or surface
    antigen positivity without evidence of active viremia (negative hepatitis B DNA)
    they may still participate in the study, but should have hepatitis serologies
    and hepatitis B DNA monitored periodically by the treating physician

    - Patients must not be receiving active systemic anticoagulation with heparin or
    warfarin; patients must be off warfarin therapy for at least 30 days prior to
    enrollment

    - Patients with class III or class IV heart failure by New York Heart Association,
    those with unstable angina, and those with uncontrolled arrhythmia are not eligible

    - Patients who have had a myocardial infarction, intracranial bleed, or stroke within
    the past 6 months are not eligible

    - Patients with human immunodeficiency virus (HIV) are eligible if their CD4 count is
    >= 350 cells/mm^3 and if they are not taking prohibited cytochrome (CYP)-interacting
    medications

    - Patients must not have any history of Richter's transformation or prolymphocytic
    leukemia (prolymphocytes in blood > 55%)

    - Patients must not require more than 20 mg prednisone or equivalent corticosteroid
    daily

    - Patients must not have uncontrolled active systemic infection requiring intravenous
    antibiotics

    - Patients must not have continued requirement for therapy with a strong cytochrome
    P450 3A4/5 (CYP3A4/5) inhibitor or inducer

    - Patients must not have a known allergy to mannitol

    - Patients must not have prior significant hypersensitivity to rituximab (not including
    infusion reactions)

    - Patients may not have had major surgery within 10 days of enrollment, or minor
    surgery within 7 days of enrollment; examples of minor surgery include dental
    surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint;
    the decision about whether a surgery is major or minor can be made at the discretion
    of the treating physician

    - Absolute neutrophil count (ANC) >= 1,000/uL unless due to bone marrow involvement

    - Aspartate aminotransferase (AST) or alanine aminotransferase (AST) =< 2.5 x upper
    limits of normal except if due to disease infiltration of the liver

    - Bilirubin =< 1.5 x upper limits of normal (unless due to liver involvement,
    hemolysis, or Gilbert's disease)

    - Creatinine clearance >= 40 mL/min

    - To be calculated by modified Cockcroft-Gault formula

    - Platelet count (untransfused) >= 30,000/uL

    Minimum Eligible Age: 65 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    PFS

    Secondary Outcome Measures

    Complete and nPR rate

    Duration of response (CR, nPR, and PR)

    Geriatric functional status (optional)

    OS

    Proportion of patients achieving a biopsy-proven CR

    Proportion of patients achieving any response to treatment (ORR [PR +nPR+ CR])

    Proportion of patients who attain MRD negative status

    Proportion of patients who experience grade 3 or higher non-hematologic toxicities

    Proportion of patients who go off treatment due to adverse reactions or refuse further treatment for lesser toxicities that inhibit their willingness to continue participation

    Quality of life

    Time to progression

    Tolerability assessed by the number of patients requiring dose modifications and/or dose delays

    Toxicity, calculated according to the frequency and severity of adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

    Trial Keywords